O-desmethyl venlafaxine (ODV), also commonly referred to as Desvenlafaxine, is chemically designated as 4-[2-dimethylamino-1-(1-hydroxycyclohexyl) ethyl]phenol. ODV is the major active metabolite of Venlafaxine and has a similar therapeutic profile to the profile of Venlafaxine, which is an active pharmaceutical ingredient indicated for the treatment of depression, anxiety and panic disorder.
ODV is presented by the structure of Formula I:

The molecule of ODV has one optically active center. As used herein, the term “ODV” refers to racemic ODV, unless stated otherwise.
Various methods are already known for the preparation of ODV or salt thereof due to its useful properties. Prior art processes for the preparation of Venlafaxine and ODV present the disadvantage of non-satisfactory purity and yield of the product. Moreover, many of the known processes for the preparation of Venlafaxine and ODV are not suitable to be adapted for large scale production. Furthermore, the compound obtained from these prior art processes often comprises significant amounts of unwanted by-products and the reaction may require a long period of time to be completed.
Several known prior art processes for the preparation of O-desmethyl venlafaxine involve demethylation of Venlafaxine. Such reaction requires crucial conditions because, on one hand, the methyl phenoxy group is very stable against nucleophilic substitution and on the other hand, the tertiary hydroxyl and the dimethylamine groups in the same molecule are susceptible to nucleophlilic attack. As a result, these processes often utilize conditions that are not suitable for large scale production.
EP-A-112 669 and its corresponding U.S. Pat. No. 4,535,186 discloses a process for the preparation of Venlafaxine and ODV by hydrogenating the O-benzyl protected precursor, which is prepared by coupling p-benzyloxyphenyl acetamide and cyclohexanone followed by reduction using lithium aluminum hydride.
This document discloses various reduction conditions as under i) Pd/C and hydrogen in ethanol+THF media, ii) Lithium aluminium hydride in acid media, iii) Rhodium Alumina in ammoniacal ethanol, iv) Borane tetrahydrofuran complex.
However the process of the above patent has the disadvantage that the addition of n-butyl lithium to 4-methoxyphenyl acetonitrile is hazardous, requiring high safety measures and great attention in handling butyl lithium, in order to avoid any unwanted incidents during the preparation process and thus said process is not suitable to be adapted for industrial manufacture.
WO 00/59851 discloses a method for the preparation of O-desmethyl venlafaxine Desvenlafaxine by reacting Venlafaxine with lithium diphenylphosphide, which is generated in-situ by slow addition of n-butyl lithium to diphenylphosphine in THF at a temperature below 0° C. THF solution of n-butyl lithium is extremely dangerous to be used in industrial production because it reacts actively with moisture in the air and generates hydrogen gas along with large amount of heat, which makes it highly explosive.
Further, WO 02/64543 discloses another method of demethylating Venlafaxine using an alkali metal salt of trialkyl borohydride, e.g. L-selectride, to obtain O-desmethyl venlafaxine. This process is not suitable for industrial production because hydrogen gas is formed during the process. Various boron-containing byproducts are also formed and pose harmful risk to the personnel and the environment.
Although each of the above documents represents an attempt to overcome the disadvantages in the prior art, there still exists a need for a cost-effective and safer process for large scale production of essentially pure O-desmethyl venlafaxine and the pharmaceutically acceptable salts thereof, which employs low toxic materials, moderate reaction conditions and capable of providing stable crystalline O-desmethyl venlafaxine and salts thereof in higher yield with higher purity.